JP2008510015A

JP2008510015A - β２アドレナリン作用性レセプターアゴニスト活性およびムスカリン性レセプターアンタゴニスト活性を有する化合物

β２アドレナリン作用性レセプターアゴニスト活性およびムスカリン性レセプターアンタゴニスト活性を有する化合物 Download PDF

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Publication number: JP2008510015A
Authority: JP; Japan
Prior art keywords: ylene; phen; alkyl; compound; formula
Prior art date: 2004-08-16
Legal status : Pending

Application number

JP2007527922A

Other languages

English (en)

Japanese (ja)

Other versions

JP2008510015A5 (https=

Inventor

マタイマーメン，

トレヴォーミッシュキ，

アダムヒューズ，

ユ−ファジ，

Original Assignee

セラヴァンス，インコーポレーテッド

Priority date

2004-08-16

Filing date

2005-08-15

Publication date

2008-04-03

2005-08-15 Application filed by セラヴァンス，インコーポレーテッド filed Critical セラヴァンス，インコーポレーテッド

2008-04-03 Publication of JP2008510015A publication Critical patent/JP2008510015A/ja

2008-09-18 Publication of JP2008510015A5 publication Critical patent/JP2008510015A5/ja

Status Pending legal-status Critical Current

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150000001875 compounds Chemical class 0.000 title claims abstract description 507
230000000694 effects Effects 0.000 title claims abstract description 56
239000000048 adrenergic agonist Substances 0.000 title abstract description 31
229940121948 Muscarinic receptor antagonist Drugs 0.000 title abstract description 27
229940126157 adrenergic receptor agonist Drugs 0.000 title abstract description 27
239000003149 muscarinic antagonist Substances 0.000 title abstract description 23
108010014499 beta-2 Adrenergic Receptors Proteins 0.000 title description 2
102100039705 Beta-2 adrenergic receptor Human genes 0.000 title 1
150000003839 salts Chemical class 0.000 claims abstract description 105
239000012453 solvate Substances 0.000 claims abstract description 53
239000003814 drug Substances 0.000 claims abstract description 26
208000019693 Lung disease Diseases 0.000 claims abstract description 17
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 11
208000006673 asthma Diseases 0.000 claims abstract description 9
125000000217 alkyl group Chemical group 0.000 claims description 164
239000000203 mixture Substances 0.000 claims description 157
-1 hydroxy, phenyl Chemical group 0.000 claims description 127
238000000034 method Methods 0.000 claims description 104
229910052739 hydrogen Inorganic materials 0.000 claims description 94
239000001257 hydrogen Substances 0.000 claims description 94
238000006243 chemical reaction Methods 0.000 claims description 74
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 71
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
239000008194 pharmaceutical composition Substances 0.000 claims description 51
229910052757 nitrogen Inorganic materials 0.000 claims description 48
125000005843 halogen group Chemical group 0.000 claims description 43
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
108060003345 Adrenergic Receptor Proteins 0.000 claims description 35
102000017910 Adrenergic receptor Human genes 0.000 claims description 35
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
125000006239 protecting group Chemical group 0.000 claims description 34
125000000753 cycloalkyl group Chemical group 0.000 claims description 33
125000002947 alkylene group Chemical group 0.000 claims description 32
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 29
125000001424 substituent group Chemical group 0.000 claims description 29
230000008569 process Effects 0.000 claims description 27
102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims description 26
108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims description 26
125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 26
RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 26
125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
125000003342 alkenyl group Chemical group 0.000 claims description 20
125000000304 alkynyl group Chemical group 0.000 claims description 20
125000004429 atom Chemical group 0.000 claims description 20
125000001153 fluoro group Chemical group F* 0.000 claims description 20
125000001072 heteroaryl group Chemical group 0.000 claims description 20
229910052799 carbon Inorganic materials 0.000 claims description 19
125000004432 carbon atom Chemical group C* 0.000 claims description 18
125000000623 heterocyclic group Chemical group 0.000 claims description 18
150000002431 hydrogen Chemical group 0.000 claims description 18
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
125000005842 heteroatom Chemical group 0.000 claims description 17
238000011282 treatment Methods 0.000 claims description 17
239000003638 chemical reducing agent Substances 0.000 claims description 16
125000004093 cyano group Chemical group *C#N 0.000 claims description 16
125000003545 alkoxy group Chemical group 0.000 claims description 15
125000000732 arylene group Chemical group 0.000 claims description 15
239000003054 catalyst Substances 0.000 claims description 15
125000005549 heteroarylene group Chemical group 0.000 claims description 15
125000003118 aryl group Chemical group 0.000 claims description 14
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
229910052760 oxygen Inorganic materials 0.000 claims description 14
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
125000001246 bromo group Chemical group Br* 0.000 claims description 13
125000004450 alkenylene group Chemical group 0.000 claims description 12
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
230000007883 bronchodilation Effects 0.000 claims description 11
239000001301 oxygen Substances 0.000 claims description 11
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
229910052717 sulfur Chemical group 0.000 claims description 11
239000011593 sulfur Chemical group 0.000 claims description 11
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 10
229940124599 anti-inflammatory drug Drugs 0.000 claims description 9
KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 9
125000000524 functional group Chemical group 0.000 claims description 9
125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 9
125000004419 alkynylene group Chemical group 0.000 claims description 8
239000002260 anti-inflammatory agent Substances 0.000 claims description 8
239000012472 biological sample Substances 0.000 claims description 8
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
230000003637 steroidlike Effects 0.000 claims description 8
KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 8
UKBZXYFHCMRXGL-UHFFFAOYSA-N (2-thiophen-3-ylphenyl)carbamic acid Chemical compound OC(=O)NC1=CC=CC=C1C1=CSC=C1 UKBZXYFHCMRXGL-UHFFFAOYSA-N 0.000 claims description 7
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
238000005859 coupling reaction Methods 0.000 claims description 7
FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 6
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 6
230000008878 coupling Effects 0.000 claims description 6
238000010168 coupling process Methods 0.000 claims description 6
125000002993 cycloalkylene group Chemical group 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 6
LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 6
AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
DCPDWJNSPCAXQB-UHFFFAOYSA-N [2-(4-methyl-1,3-thiazol-2-yl)phenyl]carbamic acid Chemical compound CC1=CSC(C=2C(=CC=CC=2)NC(O)=O)=N1 DCPDWJNSPCAXQB-UHFFFAOYSA-N 0.000 claims description 5
238000004519 manufacturing process Methods 0.000 claims description 5
239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 5
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
125000003700 epoxy group Chemical group 0.000 claims description 4
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
238000002560 therapeutic procedure Methods 0.000 claims description 4
DBYDSYSSBJUONX-UHFFFAOYSA-N (2-thiophen-2-ylphenyl)carbamic acid Chemical compound OC(=O)NC1=CC=CC=C1C1=CC=CS1 DBYDSYSSBJUONX-UHFFFAOYSA-N 0.000 claims description 3
JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 3
HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 3
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
QIKITMSTTVKETA-XIFFEERXSA-N [1-[3-[4-[[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]methyl]-3-methoxyanilino]-3-oxopropyl]piperidin-4-yl] n-(2-thiophen-3-ylphenyl)carbamate Chemical compound C=1C=C(CNC[C@H](O)C=2C=3C=CC(=O)NC=3C(O)=CC=2)C(OC)=CC=1NC(=O)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C=1C=CSC=1 QIKITMSTTVKETA-XIFFEERXSA-N 0.000 claims description 3
VNEIXXPIAQSBOC-UHFFFAOYSA-N [2-(4-bromo-1,3-thiazol-2-yl)phenyl]carbamic acid Chemical compound OC(=O)NC1=CC=CC=C1C1=NC(Br)=CS1 VNEIXXPIAQSBOC-UHFFFAOYSA-N 0.000 claims description 3
RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
229940015043 glyoxal Drugs 0.000 claims description 3
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 3
CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims description 3
125000004076 pyridyl group Chemical group 0.000 claims description 3
JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 3
229930192474 thiophene Natural products 0.000 claims description 3
150000003852 triazoles Chemical class 0.000 claims description 3
125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 claims description 2
150000001925 cycloalkenes Chemical class 0.000 claims description 2
125000002541 furyl group Chemical group 0.000 claims description 2
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
125000001544 thienyl group Chemical group 0.000 claims description 2
125000001183 hydrocarbyl group Chemical group 0.000 claims 2
OQZGLXOADHKTDN-UHFFFAOYSA-N 1-oxidopyrimidin-1-ium Chemical compound [O-][N+]1=CC=CN=C1 OQZGLXOADHKTDN-UHFFFAOYSA-N 0.000 claims 1
125000000815 N-oxide group Chemical group 0.000 claims 1
229940124597 therapeutic agent Drugs 0.000 abstract description 12
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 178
238000002360 preparation method Methods 0.000 description 138
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
230000002829 reductive effect Effects 0.000 description 100
239000000243 solution Substances 0.000 description 93
239000000047 product Substances 0.000 description 89
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
239000011541 reaction mixture Substances 0.000 description 76
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 75
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 65
239000002904 solvent Substances 0.000 description 60
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
238000003556 assay Methods 0.000 description 58
238000012360 testing method Methods 0.000 description 54
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
210000004027 cell Anatomy 0.000 description 50
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 40
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
102000005962 receptors Human genes 0.000 description 35
108020003175 receptors Proteins 0.000 description 35
239000007787 solid Substances 0.000 description 34
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
239000012044 organic layer Substances 0.000 description 33
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
239000003921 oil Substances 0.000 description 29
235000019198 oils Nutrition 0.000 description 29
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
239000012267 brine Substances 0.000 description 28
235000019439 ethyl acetate Nutrition 0.000 description 27
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
125000003386 piperidinyl group Chemical group 0.000 description 23
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 22
RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 21
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
238000009739 binding Methods 0.000 description 21
239000012528 membrane Substances 0.000 description 21
239000000725 suspension Substances 0.000 description 21
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 20
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
239000013543 active substance Substances 0.000 description 19
230000027455 binding Effects 0.000 description 19
239000010410 layer Substances 0.000 description 19
239000002245 particle Substances 0.000 description 19
238000000746 purification Methods 0.000 description 19
239000000556 agonist Substances 0.000 description 18
230000005764 inhibitory process Effects 0.000 description 18
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
239000002253 acid Substances 0.000 description 17
239000000843 powder Substances 0.000 description 17
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 16
235000019441 ethanol Nutrition 0.000 description 16
206010006482 Bronchospasm Diseases 0.000 description 15
230000007885 bronchoconstriction Effects 0.000 description 15
239000006199 nebulizer Substances 0.000 description 15
239000012071 phase Substances 0.000 description 15
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 14
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
229910052938 sodium sulfate Inorganic materials 0.000 description 14
235000011152 sodium sulphate Nutrition 0.000 description 14
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 14
241001465754 Metazoa Species 0.000 description 13
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 13
238000004128 high performance liquid chromatography Methods 0.000 description 13
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 13
229910052943 magnesium sulfate Inorganic materials 0.000 description 13
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